Journal Article
Orla M. Conneely
1Department of Molecular and Cellular Biology Baylor College of Medicine Houston, Texas 77030
*Address all correspondence and requests for reprints to: Orla M. Conneely, Ph.D., Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030.
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The steroid hormones estrogen [E] and progesterone [P] play a central role in the regulation of all aspects of female reproductive activity leading to the establishment and maintenance of pregnancy. Together, they act at the level of the hypothalamus, pituitary, ovary, and uterus to coordinate cyclic neuroendocrine gonadotropin production, ovulatory activity, and uterine development in preparation for implantation of fertilized embryos. Both hormones are also essential for postnatal mammary gland development regulating postpubertal mammary ductal morphogenesis in the case of E and pregnancy-associated lateral ductal branching and lobular alveolar differentiation in the case of P. The diverse physiological activities of E and P, however, are not restricted to the female reproductive system. Estrogen is essential for male fertility, and both hormones have been implicated in the cardiovascular, immune, and central nervous systems and in bone function. In particular, estrogen has been shown to play an important role in protection against osteoporosis in postmenopausal women [1], in the prevention of coronary heart disease [2] and in the maintenance of cognitive function [3].
In addition to positive effects in both reproductive and nonreproductive organs, estrogen plays an important role in the development of uterine cancers, and both hormones have been implicated in the development of breast cancer [4–6]. The critical role of estrogen in development of breast cancer is evidenced by the significant protective response observed in women after treatment with the antiestrogen, 4-hydroxy-tamoxifen [4-OHT] resulting in a 25% decrease in mortality and 45% decrease in incidence [6, 7].
The conflict between positive and negative activities of these hormones has fueled a search for selective receptor modulators [SRMS] for use in hormone replacement therapy that possess the capability of harnessing the tissue selective beneficial effects of the steroids while lacking adverse activities in breast and uterus.
The effects of E and P are mediated through interaction with specific intracellular receptors that are members of the nuclear receptor superfamily of transcription factors [8]. Binding of the steroids to their cognate receptors induces conformational changes in receptor structure leading to receptor dimerization, posttranslational modification, and binding to specific enhancer DNA elements in the promoters of specific genes and recruitment of coregulator proteins that interact with general transcriptional machinery to elaborate hormone-triggered changes in promoter activity. In general, agonist ligands of receptors promote binding of coactivator proteins that promote transcription initiation while binding of antagonists promote interaction with corepressor proteins that facilitate transcription repression [9]. Recent advances in our understanding of the molecular mechanisms of action of estrogen and progesterone receptors, together with molecular genetic approaches to examine the physiological consequences of receptor and coregulator protein ablation, have provided important insights into how physiological diversity of female steroid hormone action is achieved. Emerging from these studies is the general principle that the modular nature of receptors allows ligand, tissue and promoter specific interaction with select subsets of coregulators capable of elaborating distinct transcriptional and hence physiological responses to steroid signal.
Generation of functional diversity through modular receptor proteins and distinct receptor subtypes
E and P responsive tissues are initially determined by the tissue distribution of receptor proteins whose restricted spatiotemporal expression identifies tissues targeted for hormonal response. However, tissues that express receptors for estrogen and progesterone exhibit physiologically diverse responses to the same steroidal ligand. Functional diversity arises from the existence of two structurally related but nonidentical receptors for each hormone and by the ability of a single receptor subtype to elicit diverse transcriptional responses to a specific ligand. Molecular dissection of the structural and functional relationships of steroid receptors and of the mechanisms by which they interact with ligand, DNA, and the transcriptional apparatus has provided valuable information on the molecular pathways by which steroid receptors can generate functionally diverse transcriptional responses to their cognate steroid ligand. Steroid receptors including those for estrogen and progesterone have a modular protein structure consisting of distinct functional domains capable of binding steroidal ligand, dimerization of liganded receptors, interaction with hormone-responsive DNA elements, and interaction with coregulator proteins required for bridging receptors to the transcriptional apparatus [8, 9]. Binding of estrogen and progestin agonists to their receptors induces conformational changes in receptor structure that promote interaction of coactivator proteins with distinct activation domains [AFs] located within both the amino and carboxy terminal regions of the receptor. Such coactivators promote chromatin remodeling and bridging with general transcription factors resulting in the formation of productive transcription initiation complexes at the receptor responsive promoter. In contrast, binding of receptor antagonist compounds induces receptor conformational changes that render AFs nonpermissive to coactivator binding and instead promote interaction with corepressor proteins that inhibit transcriptional activity of the receptor. The ability of steroid receptors to interact with a variety of coactivator and corepressor proteins, together with the differing spatiotemporal expression of coregulators, illustrate a key role of coregulators in mediating different tissue specific responses to steroidal ligand. Finally, receptors for estrogen and progesterone can be activated in the absence of steroidal ligand by phosphorylation pathways that modulate their interactions with coregulator proteins.
Estrogen receptor isoforms
Receptors for estrogen are expressed as two structurally related subtypes, ERα and ERβ, that are encoded by two distinct genes [10, 11]. Both proteins share a high degree of amino acid conservation in their DNA binding domains [97%] and exhibit a significant but lesser degree of homology in their ligand binding domains [58%]. Two functionally distinct transactivation domains have been identified in both proteins; the first [AF1] located in the poorly conserved amino terminal domain and a second [AF2] located in the ligand binding domain. AF1 and AF2 can contribute independently and synergistically to receptor transcriptional activity in response to agonist ligands and to ligand-independent phosphorylation pathways of receptor activation and their relative activities vary depending on cellular and promoter context [12–14].
ERα and ERβ exhibit significant functional differences when examined under similar conditions in cell-based transactivation assays. Ligand binding profiles show both similar and distinct affinities of each receptor for different estrogen agonist and antagonist ligands [15]. Transcriptional responses of each receptor to ligands with which they interact with equal affinity [including 17β-estradiol] also vary significantly due in part to sequence divergence in their AF-1 domains [16] and to a differential preference of individual subtypes for specific coactivator proteins [17].
Receptor sequence divergence, however, accounts only in part for the cell- and promoter-based variations in transcriptional responses to a specific ligand. The transcription regulatory activity of either receptor in response to ligand is highly dependent on the cellular and promoter environment [12, 18]. The identification of a complex group of coregulator proteins that are recruited in a cell- and promoter-specific manner to the ligand occupied estrogen receptors reflects one of the most important recent advances in our understanding of the cellular mechanisms leading to tissue diversity in transcriptional responses to estrogen [19]. Superimposed upon this transcriptional diversity is the ability of different estrogen receptor agonist and antagonist ligands to induce distinct conformational changes in receptor structure, thereby generating a spectrum of transcriptional responses with altered cell and promoter dependency through ligand specific modulation of the conformational context of AF domains [20–23]. In addition to providing a mechanistic explanation for ability some estrogen receptor ligands [SERMS] to elicit select tissue-specific agonist activities of estrogen, the physiological implications of these findings are that ligand-specific manipulation of coregulator interaction can be used to achieve tissue and promoter specificity in transcriptional responses to receptor.
Progesterone receptor isoforms
In contrast to estrogen, receptors for progesterone are expressed as two distinct isoforms, PR-A and PR-B that arise from a single gene [24, 25]. The expression of both isoforms is conserved in rodent and humans and overlaps spatiotemporally in female reproductive tissues. However, the ratios of the individual isoforms vary in reproductive tissues as a consequence of developmental [26] and hormonal status [27] and during carcinogenesis [28, 29].
The PR-A and PR-B differ in that the PR-B protein contains an additional sequence of amino acids at its amino terminus that is not contained in PR-A. This PR-B-specific domain encodes a third transactivation function [AF3] that is absent from PR-A [30, 31]. Recent evidence has demonstrated that the presence of AF3 allows binding of a subset of coactivators to PR-B that are not efficiently recruited by progestin-bound PR-A [32]. Thus, when expressed individually in cultured cells, PR-A and PR-B display different transactivation properties that are specific to both cell type and target gene promoter context [33–36]. Agonist-bound PR-B functions as a strong activator of transcription of several PR dependent promoters and in a variety of cell types in which PR-A is inactive. Further, when both isoforms are coexpressed in cultured cells, in cell and promoter contexts in which agonist bound PR-A is inactive, the PR-A can repress the activity of PR-B. This repressor capability of PR-A also extends to other steroid receptors including ERα [31, 37]. Finally, the PR-A and PR-B proteins also respond differently to P antagonists [reviewed in Ref. 38]. While antagonist bound PR-A is inactive, antagonist bound PR-B can be converted to a strongly active transcription factor by modulating intracellular phosphorylation pathways [39–41].
Although the sequence of the ligand binding domain of the PR-A and PR-B is identical, the ability of different ligands to induce different conformational changes in PR, together with the synergistic activity of the amino and carboxy terminal activation domains [42], predicts that PR-A or PR-B selective transcriptional regulation can be achieved by manipulating ligand interactions with the carboxy terminal.
Defining the physiological spectrum of steroid receptor action
The use of genetically altered mouse mutants in which expression of individual progesterone or estrogen receptor genes has been specifically ablated has allowed direct examination of the essential roles of these receptors in mediating physiological responses to E and P. In addition to defining the individual and collective contributions of receptor subtypes to the overall repertoire of hormone action, these models facilitate examination of the contribution of specific receptor subtypes to the activities of tissue-selective receptor modulators. They have also proved a valuable means of identifying alternative pathways of steroid action that are independent of receptor activity as well as addressing the physiological significance of ligand-independent pathways of receptor activation. Finally, the receptor null mutant models serve as powerful tools to dissect the molecular genetic pathways that are regulated by these steroid receptors invivo.
Tissue-selective physiological responses to estrogen through distinct receptor subtypes
Selective ablation of ERα and ERβ in mice has provided definitive evidence that these receptor subtypes mediate distinct physiological responses to estrogen both within the reproductive tract and in nonreproductive tissues [11, 43–45]. In general, the different roles of these subtypes are a reflection of a mostly segregated spatiotemporal distribution of each receptor. ERα is the dominant subtype expressed throughout the female reproductive tract and its ablation results in infertility due to defects in sexual behavioral expression, neuroendocrine gonadotropin regulation, ovulation, uterine function, and postpubertal mammary gland morphogenesis. The ERα-subtype also plays an essential role in male fertility and mediates many of the nonreproductive activities of estrogen including regulation of bone resorption-remodeling in females, postnatal endochondral bone growth in both sexes, cardiovascular endothelial regeneration, adipogenesis, and sexual behavior [11]. In contrast to ERα, ablation of ERβ results in less severe phenotypic consequences with regard to estrogen signaling. ERβ is expressed in both the male and female reproductive tracts in a pattern largely distinct from that of ERα and its ablation results in a subfertile phenotype restricted to impaired female ovarian function [44]. Its expression and activity in this tissue are complimentary to but distinct from those of ERα. Expression of ERβ has also been detected in several nonreproductive estrogen responsive tissues including bone-forming osteoblasts, epiphyseal chondrocytes, and the cardiovascular and central nervous systems. The protein was recently shown to play an essential role in regulation of cortical neuronal survival [46] and appears to contribute together with ERα to protection against cardiovascular injury [47]
While the tissue-selective contributions of ERα and ERβ to estrogen and SERM signaling are still under active investigation, the distinct roles identified to date highlight the importance of these receptor subtypes in mediating tissue selective physiological responses to estrogen. The availability of ERα and ERβ knockout models has also allowed physiological testing and validation of the existence of alternative signaling pathways that are independent of either ligand or receptor. Thus, while uterotrophic responses stimulated by estrogen require functional ERα, the ability of some catechol and zenoestrogens to elicit such responses is independent of ERα [48, 49]. In contrast, ERα is an essential mediator of proliferative responses that are stimulated in this tissue by epidermal growth factor acting in the absence of estrogen [50]. This latter observation has provided an important physiological validation of the ligand-independent activation of estrogen receptors previously observed in cell based transactivation assays.
Tissue selectivity through progesterone receptor isoforms
The differences in transcriptional activities and coregulator interactions between the PR-A and PR-B observed in vitro predicted that these proteins also may mediate different physiological responses to progesterone. In addition, the selective ability of PR-A to inhibit transcriptional responses induced by both PR-B and the estrogen receptors suggested that PR-A has the capacity to diminish overall progesterone responsiveness in certain tissues as well as contribute to the antiestrogenic activities of progesterone previously observed in the uterus.
Null mutation of the PR gene encoding both isoforms has provided evidence of an essential role of PRs in a variety of female reproductive and nonreproductive activities [51]. Female mice lacking both PRs exhibit impaired sexual behavior, neuroendocrine gonadotropin regulation, anovulation, uterine dysfunction, and impaired ductal branching morphogenesis and lobuloalveolar differentiation of the mammary gland. PRs also play an essential role in regulation thymic involution during pregnancy and in the cardiovascular system through regulation of endothelial cell proliferation [52, 53]. Receptors for progesterone have also been identified in the central nervous system and bone where progesterone has been implicated in both cognitive function and bone maintenance. However, the essential role of PRs in these regions has not yet been confirmed.
Recent studies have begun to address the individual contributions of the PR-A and PR-B proteins to the physiological actions of progesterone using mouse mutants in which expression of the PR-A [PRAKO] or PR-B [PRBKO] isoform has been selectively ablated. Analysis of the phenotypic consequences of these mutations on female reproductive function has provided physiological proof of principle that the distinct transcriptional responses to PR-A and PR-B observed in cell-based transactivation assays are indeed reflected in an ability of the individual isoforms to elicit distinct physiological responses to progesterone. In PRAKO mice [54], the PR-B isoform functions in a tissue-specific manner to mediate a subset of the reproductive functions of PRs. Ablation of PR-A does not affect responses of the mammary gland or thymus to P but results in severe abnormalities in ovarian and uterine function. Surprisingly, the absence of PR-A in PRAKO uteri revealed an unexpected P dependent proliferative activity of PR-B in the epithelium and demonstrated that PR-A is essential to diminish both progesterone [acting via PRB] and estrogen-mediated proliferative responses in this tissue. The observation that PR-A is essential to inhibit estrogen induced proliferation in the uterus is consistent with previous observations that agonist bound PR-A is capable of inhibiting estrogen-dependent transcriptional activation in cell-based transactivation assays [37]. Notably, this inhibitory activity of PRA was tissue specific and did not extend to the mammary gland where both PR-A and PR-B act as proliferative mediators of P.
Consistent with the distinct tissue- and promoter-specific activities of PR-A and PR-B observed in tissue culture studies, the tissue-selective activities of PR-B observed in PRAKO mice were associated with an ability of this isoform to regulate a subset of progesterone responsive target genes rather than to differences in its spatiotemporal expression relative to the PR-A isoform [54].
In contrast to the reproductive defects observed in PRAKO mice, more recent studies using PRBKO mice have shown that ablation of PR-B does not affect either ovarian, uterine, or thymic responses to progesterone but results in reduced mammary ductal morphogenesis [Jericevic, B., and O. M. Conneely, unpublished observations]. Thus, PR-A is both necessary and sufficient to elicit these P-dependent reproductive responses while the PR-B isoform is required to elicit normal proliferative responses of the mammary gland to P.
From a mechanistic standpoint, the differences in physiological activities observed between the PR-A and PR-B isoforms provides an important illustration of the key role played by the amino terminal AF domains in distinguishing tissue specific responses to steroidal ligand. The results demonstrate that the inclusion or deletion of the N-terminal AF3 domain in PR is sufficient to alter tissue specific physiological responses to P.
Contribution of steroid receptor coregulators to physiological diversity of hormonal response
The characterization and mode of action of coregulator proteins that mediate the transcriptional activity of steroid receptors have been intensely examined in recent years. Agonist ligand or ligand-independent activation of receptors is associated with recruitment of a complex group of coactivators including nucleosome-disrupting histone acetyltransferases [SRC family members, PCAF and P300], mediator proteins that bridge receptor complexes with the general transcription factor complexes [e.g. DRIP/TRAP220/ARC, and mediator], an RNA helicase, p68 and components of the ubiquitin proteosome degradation system including the ubiquitin ligases, E6AP and RPF1[9, 14, 55, 56]. A growing number of corepressors associated with antagonist ligand repression of transcriptional activation have also been identified including the histone deacetylases, N-COR and SMRT [57, 58] and the estrogen receptor interacting proteins RIP140 [59] and REA [60].
Considering the complex array of coregulator proteins that can interact with both estrogen and progesterone receptors, tissue selective expression of distinct subsets of coregulator proteins would be expected to strongly influence receptor dependent biological responses in specific tissues.
Results from recent studies on the comparative spatiotemporal expression of coregulators and steroid receptors in mammalian tissues, together with the generation of knockout mouse models carrying null mutations of several coregulator proteins, have provided a key proof of concept of the essential role of coregulator proteins in mediating tissue selective physiological responses to steroidal ligand.
It is becoming apparent that the spatiotemporal expression of some coregulator proteins in steroid responsive tissues is both developmentally and hormonally controlled. For example, the expression of coactivator SRC-1 is dissociated from estrogen receptor-expressing cells during postpubertal mammary gland morphogenesis but becomes colocalized with ER-positive cells during pregnancy [61, 62]. A growing number of recent reports have also associated aberrant expression of coregulator proteins with the development of breast cancer. Significantly, these reports reveal a developing pattern of increased coactivator levels associated with tumorigenesis while the expression of corepressors is significantly decreased. For example, levels of CBP, TRAP220, and the SRC family members, SRC-2/TIF2 and AIB-1/SRC-3 are all elevated breast tumors [63, 64]. However, most notable among these is AIB-1/SRC-3, which is overexpressed in 60% of human breast cancers [65]. Conversely, levels of the corepressor, N-Cor, are decreased in invasive relative to intraductal carcinomas [64] and with the development of tamoxifen resistance in a mouse model of breast cancer [66]. Definitive evidence of the essential role of specific coregulators in mediation of tissue-specific responses to estrogen and progesterone has recently been provided by genetic ablation of a few coregulator proteins in mice. Analysis of the reproductive phenotypes of mice carrying a null mutation of SRC-1 [67] and SRC-3 [68] indicate that these coactivators regulate mostly distinct physiological activities that are due to a generally segregated spatiotemporal expression pattern of the two proteins. However, with regard to their role in E- and P-dependent reproductive physiology, deletion of either coactivator results in a partial hormone resistance in mammary gland developmental responses to E and P, indicating essential nonredundant roles for both proteins in this tissue. In contrast, only SRC-1 is expressed in the uterus and its expression is essential to elicit full growth and differentiative responses of this tissue to E and P, whereas uterine function is unaffected by deletion of SRC-3. Validation of the essential role of steroid receptor corepressors in mediating the transcriptional activity of estrogen receptors has also recently been provided by gene targeting approaches. Analysis of the transcriptional responses of mouse embryonic fibroblasts carrying a null mutation of N-CoR to the estrogen receptor antagonist, 4-OHT, demonstrated that this protein was essential to mediate the inhibitory activity of the antagonist. Ablation of N-CoR resulted in a conversion of 4-OHT to a full receptor agonist [69]. Finally, ablation of the corepressor, RIP140, in mice resulted ovulatory dysfunction and an ovarian phenotype partially overlapping that previously observed in PRKO mice, whereas uterine implantation was unaffected [70]. However, while the phenotype of RIP140 null mice supports a tissue-specific contribution of the protein to reproductive function, a direct connection between the anovulatory phenotype and the corepressor activity of RIP140 remains to be established.
Conclusions
During the past decade we have witnessed outstanding progress in our understanding of the molecular pathways by which steroid receptors elicit diverse physiological responses to hormonal signals. It is clear that tissue and promoter selectivity in hormone action is determined not only by the tissue-selective expression of distinct receptor subtypes but also of a complex group of receptor interacting coregulator proteins whose function is essential in establishing the diverse repertoire of transcriptional responses to hormone. The central role of coregulators in mediating physiological responses to estrogen and progesterone has only recently begun to be appreciated. The availability of transgenic and knock-out models to facilitate examination of the physiological roles of individual coregulators, together with the use of differential gene array technologies to identify tissue-specific downstream targets of the hormonal response, should facilitate dissection of the steroid-dependent molecular genetic pathways influenced by specific coregulators. From the limited physiological analysis carried out to date, it is becoming apparent that abnormal coregulator function may contribute to a variety of hormone- related diseases including steroid resistance syndromes, reproductive dysfunction, and tumorigenesis. Continued efforts to alter coregulator recruitment to receptors by manipulation of receptor conformation using novel ligands together with a clearer understanding of the tissue-specific molecular pathways influenced by specific coregulators should facilitate the development of new optimized tissue specific ligands for hormonal therapy.
1
Turner
RT
,Riggs
BL
,Spelsberg
TC
1994
Skeletal effects of estrogen.
Endocr Rev
15
:
275
–
300
2
Iafrati
MD
,Karas
RH
,Aronovitz
M
,Kim
S
,Sullivan
TRJ
,Lubahn
DB
,O’Donnell
TFJ
,Korach
KS
,Mendelsohn,
ME
1997
Estrogen inhibits the vascular injury response in estrogen receptorα -deficient mice.
Nature Med
3
:
545
–
548
3
Tang
MX
,Jacobs
D
,Stern
Y
,Marder
K
,Schofield
P
,Gurland
B
,Andre
H
,Mayeux,
R
1996
Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease.
Lancet
348
:
429
–
432
4
Jordan
VC
,Murphy,
CS
1990
Endocrine pharmacology of antiestrogens as antitumor agents.
Endocr Rev
11
:
578
–
610
5
Horwitz
K
,Clarke
C
1998
Estrogens and progestins in mammary development and neoplasia.
J Mammary Gland Biol Neoplasia
3
:
1
–
2
6
Jordan
VC
,Morrow
M
1999 Tamoxifen, raloxifene, and the prevention of breast cancer.Endocr Rev
20
:
253
–
278
7
Peto
R
,Boreham
J
,Clarke
M
,Davies
C
,Beral
V
2000UK and USA breast cancer deaths down 25% in year at ages 20–69 years.Lancet
355
:
1822
8
Tsai
MJ
,O’Malley
BW
1994
Molecular mechanisms of action of steroid/thyroid receptor superfamily members.
Annu Rev Biochem
63
:
451
–
486
9
McKenna
NJ
,Xu
J
,Nawaz
Z
,Tsai
SY
,Tsai
MJ
,O’Malley
BW
1999
Nuclear receptor coactivators: multiple enzymes, multiple complexes, multiple functions.
J Steroid Biochem Mol Biol
69
:
3
–
12
10
Kuiper
GG
,Enmark
E
,Pelto-Huikko
M
,Nilsson
S
,Gustafsson
JA
1996
Cloning of a novel receptor expressed in rat prostate and ovary.
Proc Natl Acad Sci USA
93
:
5925
–
5930
11
Couse
JF
,Korach,
KS
1999
Estrogen receptor null mice: what have we learned and where will they lead us? [published erratum appears in
Endocr Rev 1999 Aug: [20]:459], Endocr Rev
20
:
358
–
417
12
Tzukerman
MT
,Esty
A
,Santiso-Mere
D
,Danielian
P
,Parker
MG
,Stein
RB
,Pike
JW
,McDonnell
DP
1994
Human estrogen receptor transactivational capacity is determined by both cellular and promoter context and mediated by two functionally distinct intramolecular regions.
Mol Endocrinol
8
:
21
–
30
13
Kraus
WL
,McInerney
EM
,Katzenellenbogen
BS
1995
Ligand-dependent, transcriptionally productive association of the amino- and carboxyl-terminal regions of a steroid hormone nuclear receptor.
Proc Natl Acad Sci USA
92
:
12314
–
12318
14
Endoh
H
,Maruyama
K
,Masuhiro
Y
,Kobayashi
Y
,Goto
M
,Tai
H
,Yanagisawa
J
,Metzger
D
,Hashimoto
S
,Kato
S
1999
Purification and identification of p68 RNA helicase acting as a transcriptional coactivator specific for the activation function 1 of human estrogen receptor α.
Mol Cell Biol
19
:
5363
–
5372
15
Kuiper
GG
,Carlsson
B
,Grandien
K
,Enmark
E
,Haggblad
J
,Nilsson
S
,Gustafsson
JA
1997
Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptorsα and β.
Endocrinology
138
:
863
–
870
16
McInerney
EM
,Weis
KE
,Sun
J
,Mosselman
S
,Katzenellenbogen
BS
1998
Transcription activation by the human estrogen receptor subtype beta [ER β] studied with ER β and ER α receptor chimeras.
Endocrinology
139
:
4513
–
4522
17
Suen
CS
,Berrodin
TJ
,Mastroeni
R
,Cheskis
BJ
,Lyttle
CR
,Frail,
DE
1998
A transcriptional coactivator, steroid receptor coactivator-3, selectively augments steroid receptor transcriptional activity.
J Biol Chem
273
:
27645
–
27653
18
Katzenellenbogen
BS
,Montano
MM
,Ediger
TR
,Sun
J
,Ekena
K
,Lazennec
G
,Martini
PG
,McInerney
EM
,Delage-Mourroux
R
,Weis
K
,Katzenellenbogen,
JA
2000
Estrogen receptors: selective ligands, partners, and distinctive pharmacology.
Rec Prog Hormone Res
55
:
163
–
193
19
McKenna
NJ
,Lanz
RB
,O’Malley
BW
1999
Nuclear receptor coregulators: cellular and molecular biology.
Endocr Rev
20
:
321
–
344
20
McDonnell
DP
,Clemm
DL
,Hermann
T
,Goldman
ME
,Pike
JW
1995
Analysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens.
Mol Endocrinol
9
:
659
–
669
21
Brzozowski
AM
,Pike
AC
,Dauter
Z
,Hubbard
RE
,Bonn
T
,Engstrom
O
,Ohman
L
,Greene
GL
,Gustafsson
JA
,Carlquist
M
1997
Molecular basis of agonism and antagonism in the oestrogen receptor.
Nature
389
:
753
–
758
22
Paige
LA
,Christensen
DJ
,Gron
H
,Norris
JD
,Gottlin
EB
,Padilla
KM
,Chang
CY
,Ballas
LM
,Hamilton
PT
,McDonnell
DP
,Fowlkes
DM
1999
Estrogen receptor [ER] modulators each induce distinct conformational changes in ER α and ER β.
Proc Natl Acad Sci USA
96
:
3999
–
4004
23
Norris
JD
,Paige
LA
,Christensen
DJ
,Chang
CY
,Huacani
MR
,Fan
D
,Hamilton
PT
,Fowlkes
DM
,McDonnell
DP
1999
Peptide antagonists of the human estrogen receptor.
Science
285
:
744
–
746
24
Conneely
OM
,Kettelberger
DM
,Tsai
MJ
,Schrader
WT
,O’Malley
BW
1989
The chicken progesterone receptor A and B isoforms are products of an alternate translation initiation event.
J Biol Chem
264
:
14062
–
14064
25
Kastner
P
,Krust
A
,Turcotte
B
,Stropp
U
,Tora
L
,Gronemeyer
H
,Chambon
P
1990
Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B.
Embo J
9
:
1603
–
1614
26
Shyamala
G
,Schneider
W
,Schott
D
1990
Developmental regulation of murine mammary progesterone receptor gene expression.
Endocrinology
126
:
2882
–
2889
27
Duffy
DM
,Wells
TR
,Haluska
GJ
,Stouffer
RL
1997
The ratio of progesterone receptor isoforms changes in the monkey corpus luteum during the luteal phase of the menstrual cycle.
Biol Reprod
57
:
693
–
699
28
Brandon
DD
,Bethea
CL
,Strawn
EY
,Novy
MJ
,Burry
KA
,Harrington
MS
,Erickson
TE
,Warner
C
,Keenan
EJ
,Clinton
GM
1993
Progesterone receptor messenger ribonucleic acid and protein are overexpressed in human uterine leiomyomas.
Am J Obstet Gynecol
169
:
78
–
85
29
Graham
JD
,Yeates
C
,Balleine
RL
,Harvey
SS
,Milliken
JS
,Bilous
AM
,Clarke
CL
1996
Progesterone receptor A, and B protein expression in human breast cancer.
J Steroid Biochem Mol Biol
56
:
93
–
98
30
Sartorius
CA
,Melville
MY
,Hovland
AR
,Tung
L
,Takimoto
GS
,Horwitz
KB
1994
A third transactivation function [AF3] of human progesterone receptors located in the unique N-terminal segment of the B-isoform.
Mol Endocrinol
8
:
1347
–
1360
31
Wen
DX
,Xu
YF
,Mais
DE
,Goldman
ME
,McDonnell
DP
1994
The A and B isoforms of the human progesterone receptor operate through distinct signaling pathways within target cells.
Mol Cell Biol
14
:
8356
–
8364
32
Giangrande
PH
,Kimbrel
EA
,Edwards
DP
,McDonnell
DP
2000
The opposing transcriptional activities of the two isoforms of the human progesterone receptor are due to differential cofactor binding.
Mol Cell Biol
20
:
3102
–
3115
33
Tora
L
,Gronemeyer
H
,Turcotte
B
,Gaub
MP
,Chambon
P
1988
The N-terminal region of the chicken progesterone receptor specifies target gene activation.
Nature
333
:
185
–
188
34
Meyer
ME
,Quirin-Stricker
C
,Lerouge
T
,Bocquel
MT
,Gronemeyer
H
1992
A limiting factor mediates the differential activation of promoters by the human progesterone receptor isoforms.
J Biol Chem
267
:
10882
–
10887
35
Vegeto
E
,Shahbaz
MM
,Wen
DX
,Goldman
ME
,O’Malley
BW
,McDonnell
DP
1993
Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function.
Mol Endocrinol
7
:
1244
–
1255
36
Hovland
AR
,Powell
RL
,Takimoto
GS
,Tung
L
,Horwitz
KB
1998
An N-terminal inhibitory function IF, suppresses transcription by the A-isoform but not the B-isoform of human progesterone receptors.
J Biol Chem
273
:
5455
–
5460
37
McDonnell
DP
,Shahbaz
MM
,Vegeto
E
,Goldman
ME
1994
The human progesterone receptor A-form functions as a transcriptional modulator of mineralocorticoid receptor transcriptional activity.
J Steroid Biochem Mol Biol
48
:
425
–
432
38
Giangrande
PH
,McDonnell
DP
1999
The A and B isoforms of the human progesterone receptor: two functionally different transcription factors encoded by a single gene.
Recent Prog Horm Res
54
:
291
–
313
39
Sartorius
CA
,Groshong
SD
,Miller
LA
,Powell
RL
,Tung
L
,Takimoto
GS
,Horwitz
KB
1994
New T47D breast cancer cell lines for the independent study of progesterone B- and A-receptors: only antiprogestin-occupied B- receptors are switched to transcriptional agonists by cAMP.
Cancer Res
54
:
3868
–
3877
40
Musgrove
EA
,Hamilton
JA
,Lee
CS
,Sweeney
KJ
,Watts
CK
,Sutherland
RL
1993
Growth factor, steroid, and steroid antagonist regulation of cyclin gene expression associated with changes in T-47D human breast cancer cell cycle progression.
Mol Cell Biol
13
:
3577
–
3587
41
Beck
CA
,Weigel
NL
,Moyer
ML
,Nordeen
SK
,Edwards
DP
1993
The progesterone antagonist RU486 acquires agonist activity upon stimulation of cAMP signaling pathways.
Proc Natl Acad Sci USA
90
:
4441
–
4445
42
Tetel
MJ
,Giangrande
PH
,Leonhardt
SA
,McDonnell
DP
,Edwards
DP
1999
Hormone-dependent interaction between the amino- and carboxyl-terminal domains of progesterone receptor in vitro and in vivo.
Mol Endocrinol
13
:
910
–
924
43
Lubahn
DB
,Moyer
JS
,Golding
TS
,Couse
JF
,Korach
KS
,Smithies
O
1993
Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene.
Proc Natl Acad Sci USA
90
:
11162
–
11166
44
Krege
JH
,Hodgin
JB
,Couse
JF
,Enmark
E
,Warner
M
,Mahler
JF
,Sar
M
,Korach
KS
,Gustafsson
JA
,Smithies
O
1998
Generation and reproductive phenotypes of mice lacking estrogen receptor β.
Proc Natl Acad Sci USA
95
:
15677
–
15682
45
Dupont
S
,Krust
A
,Gansmuller
A
,Dierich
A
,Chambon
P
,Mark
M
2000
Effect of single and compound knockouts of estrogen receptors alpha [ERα] and β [ERβ] on mouse reproductive phenotypes.
Development
127
:
4277
–
4291
46
Wang
L
,Andersson
S
,Warner
M
,Gustafsson
JA
2001
Morphological abnormalities in the brains of estrogen receptor β knockout mice.
Proc Natl Acad Sci USA
98
:
2792
–
2796
47
Mendelsohn
ME
2000
Mechanisms of estrogen action in the cardiovascular system.
J Steroid Biochem Mol Biol
74
:
337
–
343
48
Das
SK
,Taylor
JA
,Korach
KS
,Paria
BC
,Dey
SK
,Lubahn
DB
1997
Estrogenic responses in estrogen receptor-α deficient mice reveal a distinct estrogen signaling pathway.
Proc Natl Acad Sci USA
94
:
12786
–
12791
49
Ghosh
D
,Taylor
JA
,Green
JA
,Lubahn
DB
1999
Methoxychlor stimulates estrogen-responsive messenger ribonucleic acids in mouse uterus through a non-estrogen receptor [non-ER] α and non-ERβ mechanism.
Endocrinology
140
:
3526
–
3533
50
Curtis
SW
,Washburn
T
,Sewall
C
,DiAugustine
R
,Lindzey
J
,Couse
JF
,Korach,
K
1996
Physiological coupling of growth factor and steroid receptor signaling pathways: estrogen receptor knockout mice lack estrogen-like response to epidermal growth factor.
Proc Natl Acad Sci USA
93
:
12626
–
12630
51
Lydon
JP
,DeMayo
FJ
,Funk
CR
,Mani
SK
,Hughes
AR
,Montgomery Jr
CA
,Shyamala
G
,Conneely
OM
,O’Malley
BW
1995
Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities.
Genes Dev
9
:
2266
–
2278
52
Tibbetts
TA
,DeMayo
F
,Rich
S
,Conneely
OM
,O’Malley
BW
1999
Progesterone receptors in the thymus are required for thymic involution during pregnancy and for normal fertility.
Proc Natl Acad Sci USA
96
:
12021
–
12026
53
Vazquez
F
,Rodriguez-Manzaneque
JC
,Lydon
JP
,Edwards
DP
,O’Malley
BW
,Iruela-Arispe,
ML
1999
Progesterone regulates proliferation of endothelial cells.
J Biol Chem
274
:
2185
–
2192
54
Mulac-Jericevic
B
,Mullinax
RA
,DeMayo
FJ
,Lydon
JP
,Conneely
OM
2000
Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B isoform.
Science
289
:
1751
–
1754
55
Nawaz
Z
,Lonard
DM
,Smith
CL
,Lev-Lehman
E
,Tsai
SY
,Tsai
MJ
,O’Malley
BW
1999
The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily.
Mol Cell Biol
19
:
1182
–
1189
56
Imhof
MO
,McDonnell
DP
1996
Yeast RSP5 and its human homolog hRPF1 potentiate hormone dependent activation of transcription by human progesterone and glucocorticoid receptors.
Mol Cell Biol
16
:
2594
–
2605
57
Horlein
AJ
,Naar
AM
,Heinzel
T
,Torchia
J
,Gloss
B
,Kurokawa
R
,Ryan
A
,Kamei
Y
,Soderstrom
M
,Glass
CK
,Rosenfeld
M
1995
Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor.
Nature
377
:
397
–
404
58
Chen
JD
,Evans
RM
1995
A transcriptional co-repressor that interacts with nuclear hormone receptors.
Nature
377
:
454
–
457
59
Cavailles
V
,Dauvois
S
,L’Horset
F
,Lopez
G
,Hoare
S
,Kushner
PJ
,Parker
MG
1995
Nuclear factor RIP140 modulates transcriptional activity by the oestrogen receptor.
EMBO J
14
:
3741
–
3751
60
Montano
MM
,Ekena
K
,Delage-Mourroux
R
,Chang
W
,Martini
P
,Katzenellenbogen
BS
1999
An estrogen receptor-selective coregulator that potentiates the effectiveness of antiestrogens and represses the activity of estrogens.
Proc Natl Acad Sci USA
96
:
6947
–
6952
61
Shim
WS
,DiRenzo
J
,DeCaprio
JA
,Santen
RJ
,Brown
M
,Jeng
MH
1999
Segregation of steroid receptor coactivator-1 from steroid receptors in mammary epithelium.
Proc Natl Acad Sci USA
96
:
208
–
213
62
Shim
W-S
,Chang
L-Y
,Zhang
Q
,Turner
MA
,Brown
M
,Jeng
M-H
Segregation and colocalization of steroid receptor coactivators with estrogen receptor α during mammary gland development
,
Program of the 82nd Annual Meeting of The Endocrine Society
,
Toronto, Canada
, p
343
[Abstract 1423]
63
Zhu
Y
,Qi
C
,Jain
S
,Le Beau
MM
,Espinosa
R
,Atkins
GB
,Lazar
MA
,Yeldandi
AV
,Rao
MS
,Reddy
JK
1999
Amplification and overexpression of peroxisome proliferator-activated receptor binding protein [PBP/PPARBP] gene in breast cancer.
Proc Natl Acad Sci USA
96
:
10848
–
10853
64
Kurebayashi
J
,Otsuki
T
,Kunisue
H
,Tanaka
K
,Yamamoto
S
,Sonoo
H
2000
Expression levels of estrogen receptor-α, estrogen receptor-β, coactivators, and corepressors in breast cancer.
Clin Cancer Res
6
:
512
–
518
65
Anzick
SL
,Kononen
J
,Walker
RL
,Azorsa
DO
,Tanner
MM
,Guan
XY
,Sauter
G
,Kallioniemi
OP
,Trent
JM
,Meltzer
PS
1997
AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer.
Science
277
:
965
–
968
66
Lavinsky
RM
,Jepson
K
,Heinzel
T
,Torchia
J
,Mullen
TM
,Schiff
R
,Del-Rio
AL
,Ricote
M
,Ngo
S
,Gemsch
J
,Hilsenbeck
SG
,Osborne
CK
,Glass
CK
,Rosenfeld
MG
,Rose
DW
1998
Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes.
Proc Natl Acad Sci USA
95
:
2920
–
2925
67
Xu
J
,Qiu
Y
,DeMayo
FJ
,Tsai
SY
,Tsai
MJ
,O’Malley
BW
1998
Partial hormone resistance in mice with disruption of the steroid receptor coactivator-1 [SRC-1] gene.
Science
279
:
1922
–
1925
68
Xu
J
,Liao
L
,Ning
G
,Yoshida-Komiya
H
,Deng
C
,O’Malley
BW
2000
The steroid receptor coactivator SRC-3 [p/CIP/RAC3/AIB1/ACTR/TRAM-1] is required for normal growth, puberty, female reproductive function, and mammary gland development.
Proc Natl Acad Sci USA
97
:
6379
–
6384
69
Jepsen
K
,Hermanson
O
,Onami
TM
,Gleiberman
AS
,Lunyak
V
,McEvilly
RJ
,Kurokawa
R
,Kumar
V
,Liu
F
,Seto
E
,Hedrick
SM
,Mandel
G
,Glass
CK
,Rose
DW
,Rosenfeld
MG
2000
Combinatorial roles of the nuclear receptor corepressor in transcription and development.
Cell
102
:
753
–
763
70
White
R
,Leonardsson
G
,Rosewell
I
,Jacobs
MA
,Milligan
S
,Parker
M
2000
The nuclear receptor co-repressor Nrip1 [RIP140] is essential for female fertility.
Nature Medicine
6
:
1368
–
1373
Copyright © 2001 by The Endocrine Society
Copyright © 2001 by The Endocrine Society
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